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Trial registered on ANZCTR


Trial ID
ACTRN12615000533594
Ethics application status
Approved
Date submitted
21/01/2015
Date registered
27/05/2015
Date last updated
5/02/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
Haemodynamic Effects Of Intravenous Paracetamol In Healthy Volunteers
Scientific title
Haemodynamic Effects Of Intravenous Paracetamol In Healthy Volunteers
Secondary ID [1] 282514 0
NIL
Universal Trial Number (UTN)
U1111-1166-3985
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Blood pressure in Healthy Volunteers 289176 0
Cardiac output in Health Volunteers 295153 0
Systemic vascular resistance in Healthy volunteers 295154 0
Condition category
Condition code
Cardiovascular 294377 294377 0 0
Normal development and function of the cardiovascular system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Paracetamol is one of the most commonly used medications in the world. The intravenous formulation is the preferred method of administration in the intraoperative and immediate postoperative periods.

1 gram of Intravenous paracetamol (Actavis, North Adelaide, SA) is manufactured in a 100 ml vial that contains the following in its formulations:
Paracetamol = 1g, Mannitol = 3.91g, Cysteine hydrochloride monohydrate, Dibasic dihydrate, sodium phosphate, sodium hydroxide, hydrochloric acid, water for injections

It is unknown if intravenous paracetamol results in adverse effects of haemodynamics i.e blood pressure, cardiac output, stroke volume and systemic vascular resistence

Therefore we will perform a triple crossover study to investigate this question.

Each healthy volunteer will receive the following 3 interventions on 3 separate days. The days will be between 1 and 7 days part. i.e there will be a washout period of between 1 and 7 days. The infusions will be administered over a 15 minute period.

The three interventions are:

1. 1 gram intravenous paracetamol (Actavis, North Adelaide, SA) (100 ml total volume)
2. Mannitol 3.9 grams (100 ml total volume)
3. Normal saline (0.9%) (100 ml total volume)

A non-invasive haemodynamic monitoring device (Edwards Lifescience Nexfin Clearsite) will be attached to the participant's wrist and middle finger. It will continuously monitor the participant's blood pressure (mean, systolic and diastolic), cardiac output, stroke volume and systemic vascular resistance.

The effects of intravenous paracetamol on haemodynamics will be measured before the infusion, during the 15 minute infusion, and for 60 minutes after the infusion.
Intervention code [1] 287171 0
Treatment: Drugs
Comparator / control treatment
Mannitol 3.9 grams intravenously (administered in 100mL of distilled water over a 15 minute period)

Saline (0.9%) intravenously (administered in 100mL of distilled water over a 15 minute period)


Control group
Placebo

Outcomes
Primary outcome [1] 289600 0
Systolic blood pressure using the Edwards Lifesciences ClearSite Advanced haemodynamic monitor.
Timepoint [1] 289600 0
Baseline just before administration of each intervention;
During the 15 minute infusion period of each intervention;
For 60 minutes after the infusions have been administered.
Primary outcome [2] 294168 0
Diastolic blood pressure measured using the Edwards Lifesciences ClearSite Advanced haemodynamic monitor
Timepoint [2] 294168 0
Baseline just before administration of each intervention;
During the 15 minute infusion period of each intervention;
For 60 minutes after the infusions have been administered.
Primary outcome [3] 294169 0
Mean arterial blood pressure measured using the Edwards Lifesciences ClearSite Advanced haemodynamic monotoring
Timepoint [3] 294169 0
Baseline just before administration of each intervention;
During the 15 minute infusion period of each intervention;
For 60 minutes after the infusions have been administered.
Secondary outcome [1] 302824 0
Cardiac Output measured the Edwards Lifesciences ClearSite Advanced haemodynamic monitor.
Timepoint [1] 302824 0
1. Baseline just before administration of each intervention
2. During the 15 minute infusion period of each intervention
3. For 60 minutes after the infusions have been administered
Secondary outcome [2] 302825 0
Cardiac Index measured the Edwards Lifesciences ClearSite Advanced haemodynamic monitor.
Timepoint [2] 302825 0
1. Baseline just before administration of each intervention
2. During the 15 minute infusion period of each intervention
3. For 60 minutes after the infusions have been administered
Secondary outcome [3] 312518 0
Stroke volume measured the Edwards Lifesciences ClearSite Advanced haemodynamic monitor.
Timepoint [3] 312518 0
1. Baseline just before administration of each intervention
2. During the 15 minute infusion period of each intervention
3. For 60 minutes after the infusions have been administered
Secondary outcome [4] 312519 0
Systemic vascular resistance measured the Edwards Lifesciences ClearSite Advanced haemodynamic monitor.
Timepoint [4] 312519 0
1. Baseline just before administration of each intervention
2. During the 15 minute infusion period of each intervention
3. For 60 minutes after the infusions have been administered
Secondary outcome [5] 312520 0
Plasma Osmolality using the a ABL 800 Laboratory Monitor
Timepoint [5] 312520 0
1. Baseline just before administration of each intervention
2.Immediately after the 15 minute infusion period of each intervention
3. 60 minutes after the infusions have been administered

Eligibility
Key inclusion criteria
1. Adults (age >18 years but less than 60 years)
2. Healthy Volunteers
3. No regular medications
Minimum age
18 Years
Maximum age
60 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Paracetamol use 24 hours prior to trial (in paracetamol only or in combination therapy)

Pregnancy

Chronic renal impairment (Creatinine >120 umol/L)

Chronic liver disease (ALT >100IU/L)

Morbid obesity (BMI >35kg/m2)

Known allergic reaction to IV paracetamol, mannitol or normal saline

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation will be concealment will be by means of sealed opaque envelopes. The sealed envelopes will be stored in a locked facility in the department of Anaesthesia at Austin Hospital, where the trial is being conducted. After informed participant consent has been obtained, an independent research assistant/investigator will open the sealed envelope which will contain the randomisation group.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a computer software (i.e. computerised sequence generation) will be performed by the Principle Investigator. The computer will be password protected and located in the Department of Anaesthesia Research Facilities at Austin Hospital. Participants will be randomly allocated to one of the three infusion arms:

1. Paracetamol 1 gram (100 ml total volume)
2. Mannitol 3.9 grams (100 ml total volume)
3. Normal saline (0.9%) (100 ml total volume)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
NIL
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
We will recruit 24 patients in total.

Sample size for the study will be calculated based on healthy volunteer database from our hospital. With a mean blood pressure of 120 mmHg, and a SD of 10 mmHg, if we were to demonstrate a mean difference between the groups of 10 mmHg, with an alpha level of 0.05, and beta value of 0.9, a total of 24 participants will be required.

Repeated measures analysis of variance modelling will be performed by fitting the main effects for treatment (i.e. paracetamol, mannitol, NS) and time and an interaction between treatment and time to determine if the 3 treatments behaved differently over time. Within each variable, analysis will be stratified by period (pre-infusion, infusion, observation) so there were 3 sets of analysis for each variable.

Because there will be 3 groups, the overall p-value for a group effect will simply answer the question "are these 3 groups significantly different from each other overall"; it will not inform us specifically where the differences are. For this information we will perform post-hoc analyses, looking for specific pairwise comparisons (paracetamol vs. mannitol, paracetamol vs. NS, mannitol vs. NS).

Modelling was performed using the PROC Mixed procedure in SAS version 9.2 (SAS Institute Inc., Cary, NC, USA). Mean and standard deviations for the three plasma osmolality levels will be calculated using the T-test function on Microsoft Excel software. Continuous data will be tested for normal distribution using the D’Agostino-Pearson omnibus test.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 1016 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 6891 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 287297 0
Hospital
Name [1] 287297 0
Austin Hospital
Address [1] 287297 0
Department of Intensive Care
Studley Road, Heidelbeg, Victoria, 3084
Country [1] 287297 0
Australia
Primary sponsor type
Hospital
Name
Austin Hospital
Address
Department of Intensive Care
Studley Road, Heidelbeg, Victoria, 3084
Country
Australia
Secondary sponsor category [1] 286049 0
None
Name [1] 286049 0
Address [1] 286049 0
Country [1] 286049 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289272 0
Austin Health Research Ethics Unit
Ethics committee address [1] 289272 0
Austin Health Research Ethics Unit
Austin Health
145 Studley Road
Heidelberg
Victoria, 3084
Ethics committee country [1] 289272 0
Australia
Date submitted for ethics approval [1] 289272 0
26/03/2013
Approval date [1] 289272 0
06/06/2013
Ethics approval number [1] 289272 0
H2013/05005

Summary
Brief summary
Intravenous paracetamol is ubiquitously used in hospitals as an antipyretic and analgesic worldwide. It is administered to a wide array of patients including those undergoing major surgeries and the critically ill due to its minimal side effect profile. However, recent studies have provided compelling evidence for a re-evaluation of paracetamol use in this setting as it has been found to cause hypotension in intensive care patients. Importantly, there is a paucity of guidance regarding its haemodynamic safety in surgical and critically ill patients. This may be due to a lack of double-blinded, randomised controlled trials in these settings as well as in healthy patient cohorts for comparative studies. In addition, a previous study found that oral effervescent paracetamol tablets produced hypertension in patients which study investigators linked to the high sodium content in the effervescent formulation. It is therefore important to acknowledge that excipients (pharmacologically inactive compounds that act as vehicles for the active compound in the drug) may affect blood pressure. There is no existing literature that has addressed the potential for the high mannitol content of intravenous paracetamol to produce haemodynamic effects.

Hypothesis:
Paracetamol (1g IV) and mannitol (3.91g mannitol IV) will have adverse effects on blood pressure in healthy volunteers compared to 0.9% normal saline.

No of participants: 24

No of recruiting hospitals: 1

Randomization: In this triple-cross over study, participants will be randomized in a 1:1:1 fashion via a computer generated randomization program to receive 1 treatment from each of the treatment arms. The treatment arms include:
1) Control (100mL 0.9% normal saline)
2) IV paracetamol (100mL paracetamol and mannitol 3.91g)
3) IV Mannitol treatment (100ml mannitol 3.91g)

Blinding: This is a double-blinded clinical trial. This study requires the use of 100mL blinded fluid vials. These vials will look identical in all treatment groups. Depending on randomization, IV paracetamol, 0.9% normal saline or mannitol will be transferred into the blinded vials just prior to IV infusion. Preparation of the blinded vials will be conducted by an anaesthesia nurse who will not be involved in the data collection. The participants, sampling anaesthetist and data analyst will be blinded to the assignment of treatment.

Primary endpoint: Changes in haemodynamics: Mean, systolic and diastolic blood pressure
Secondary endpoints: Cardiac output and cardiac index, stroke volume, systemic vascular resistance, plasma osmolality

Other data collected: Patient characteristics and adverse events
Trial website
NIL
Trial related presentations / publications
1. Chiam E, Weinberg L, Bellomo R. Haemodynamic effect of intravenous paracetamol in healthy Volunteers. European J Anaesthesiology 2015; 32 e-suppl 53: 15-16

2. Chiam L, Weinberg L, Bailey M, McNicol L, Bellomo R. Haemodynamic effect of intravenous paracetamol in healthy volunteers. A single centre blinded randomized controlled trial. Br J Clin Pharmacol 2015; Nov 25. doi: 10.1111/bcp.12841
Public notes

Contacts
Principal investigator
Name 40114 0
A/Prof Laurence Weinberg
Address 40114 0
Department of Anaesthesia Austin Hospital Studley Road Heidelberg, 3084, Victoria
Country 40114 0
Australia
Phone 40114 0
+61 3 94965000
Fax 40114 0
+61 3 94596421
Email 40114 0
Laurence.Weinberg@austin.org.au
Contact person for public queries
Name 40115 0
A/Prof Laurence Weinberg
Address 40115 0
Department of Anaesthesia Austin Hospital Studley Road Heidelberg, 3084, Victoria
Country 40115 0
Australia
Phone 40115 0
+61 3 94965000
Fax 40115 0
+61 3 94596421
Email 40115 0
Laurence.Weinberg@austin.org.au
Contact person for scientific queries
Name 40116 0
Dr Laurence Weinberg
Address 40116 0
Department of Anaesthesia Austin Hospital Studley Road Heidelberg, 3084, Victoria
Country 40116 0
Australia
Phone 40116 0
+61 3 94965000
Fax 40116 0
+61 3 94596421
Email 40116 0
Laurence.Weinberg@austin.org.au